title: Palmitoylethanolamide improves colon inflammation through an enteric glia/toll like receptor 4-dependent PPAR-α activation.
abstract: OBJECTIVE
  Enteric glia activation has been reported to amplify intestinal inflammation via the enteroglial-specific S100B protein. This neurotrophin promotes macrophage recruitment in the mucosa, amplify colonic inflammation and interacts with toll-like receptors (TLR). Molecules inhibiting S100B-driven enteric activation might mitigate the course of ulcerative colitis (UC). This study aims to investigate the effects of palmitoylethanolammide (PEA), a drug able to counteract astroglial activation in the central nervous system, on intestinal inflammation, in humans and mice.
  
  
  METHODS
  Mouse models of dextran sodium sulphate (DSS)-induced colitis, colonic biopsies deriving from UC patients and primary cultures of mouse and human enteric glial cells (EGC), have been used to assess the effects of PEA, alone or in the presence of specific PPARα or PPARγ antagonists, on: macroscopic signs of UC (DAI score, colon length, spleen weight, macrophages/neutrophils infiltration); the expression and release of proinflammatory markers typical of UC; TLR pathway in EGCs.
  
  
  RESULTS
  PEA treatment improves all macroscopic signs of UC and decreases the expression and release of all the proinflammatory markers tested. PEA anti-inflammatory effects are mediated by the selective targeting of the S100B/TLR4 axis on ECG, causing a downstream inhibition of nuclear factor kappa B (NF-kB)-dependent inflammation. Antagonists at PPARα, but not PPARγ, abolished PEA effects, in mice and in humans.
  
  
  CONCLUSIONS
  Because of its lack of toxicity, its ability in reducing inflammation and its selective PPARα action, PEA might be an innovative molecule to broaden pharmacological strategies against UC.
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', La Sapienza University of Rome, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Esposito
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', La Sapienza University of Rome, Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Capoccia
authors.affiliation: Department of Clinical Medicine and Surgery, 'Federico II' University of Naples, Naples, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Turco
authors.affiliation: Department of Clinical Medicine and Surgery, 'Federico II' University of Naples, Naples, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Palumbo
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.affiliation: La Sapienza University of Rome, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Steardo
authors.affiliation: Department of Clinical Medicine and Surgery, 'Federico II' University of Naples, Naples, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Cuomo
authors.affiliation: Department of Clinical Medicine and Surgery, 'Federico II' University of Naples, Naples, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sarnelli
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', La Sapienza University of Rome, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Steardo
mesh_terms: D000577:Amides; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012809:Colon, Sigmoid / Q000737:chemistry / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016264:Dextran Sulfate; D015232:Dinoprostone / Q000378:metabolism; D063388:Endocannabinoids / Q000494:pharmacology / Q000627:therapeutic use*; D004983:Ethanolamines / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000187:drug effects; D009569:Nitric Oxide / Q000032:analysis / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D010169:Palmitic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D012007:Rectum / Q000737:chemistry / Q000473:pathology; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism*; D012720:Severity of Illness Index; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D002722:Chlorobenzenes
chemical_list: D000577:Amides; D000813:Anilides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051546:Cyclooxygenase 2; D016264:Dextran Sulfate; D015232:Dinoprostone; D063388:Endocannabinoids; D004983:Ethanolamines; D005904:Glial Fibrillary Acidic Protein; D007211:Indoles; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D047493:PPAR alpha; D047495:PPAR gamma; D010169:Palmitic Acids; D064568:S100 Calcium Binding Protein beta Subunit; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C457499:2-chloro-5-nitrobenzanilide; C579160:S100B protein, human; C528900:glial fibrillary astrocytic protein, mouse; C060893:MK-886; D002722:Chlorobenzenes; C005958:palmidrol
keywords: ENTERIC NERVOUS SYSTEM; GUT INFLAMMATION; NERVOUS CONTROL OF INTESTINAL FUNCTIONS; ULCERATIVE COLITIS